1. Field of the Invention
This invention relates to the prevention of post-ischemic tissue damage.
2. Description of the Prior Art
Ischemic and post-ischemic tissue damage results when blood flow into bodily tissues and/or organs is blocked and the tissue becomes hypoxic. Upon restoration of normal blood flow, i.e., reperfusion, large amounts of toxic oxygen free radicals (O.sub.2.sup.-) are produced which cause significant tissue and/or organ damage and impaired function. Ischemia-induced tissue damage is now believed to be a major and medically significant complication in a wide variety of cardiovascular, central nervous system, and intestinal disease processes. In addition, post-ischemic tissue damage is also a medically significant problem in organ transplantation and circulatory shock. (McCord, J. M.: "Oxygen-Derived Free Radicals in Post-Ischemic Tissue Injury," New England Journal of Medicine, 312:154-163, 1985.)
The toxic oxygen radicals responsible for post-ischemic tissue injury originate from two biochemically different sources. Large amounts of radicals are produced in ischemic and reperfused tissue as a byproduct of the enzymatic conversion of hypoxanthine to xanthine by xanthine oxidase and also as metabolic products from activated blood neutrophils also known as activated polymorphonuclear leukocytes. There is substantial experimental evidence implicating both sources as major contributors to the pathology of ischemia-reperfusion tissue damage. (Hill, J. H., Ward, P.A.: "The Phlogistic Role of C3 Leukotactic Fragments in Myocardial Infarcts of Rats," Journal Exp. Medicine, 133:885-900, 1971; Rossen, R. D. et al: "Selective Accumulation of First Component of Complement and Leukocytes in Ischemic Canine Heart Muscle," Circ. Res. 57:119-129, 1985; Bednar, M., Smith, B., Pinto, A. and Mullane, K. M.: "Nafazatrom-Induced Salvage of Ischemic Myocardium in Anesthetized Dogs is Mediated Through Inhibition of Neutrophil Function," Circ. Res. 57:131-141, 1985.) Moreover, in myocardial ischemia due to permanent occlusion of a coronary artery, oxygen free radicals and neutrophils are believed to cause tissue damage. The oxygen free radicals would be generated in ischemic tissue from oxygen delivered to the tissue via the coronary collateral circulation (Downey et al: "Infarct size limitation by the xanthine oxidase inhibitor allopurinol in closed chest dogs with small infarcts", Cardiovasc. Res. 19, 686-698, 1985.).
Therapeutic approaches to treating post-ischemic tissue injury have concentrated initially on drugs that selectively inhibit xanthine oxidase (e.g., allopurinol) and, more recently, on drugs that inhibit O.sub.2.sup.- production by activated polymorphonuclear leukocytes (e.g., aprotinin, nafazatrom, ibuprofen). Presently, there are no reports in the literature of any drug that inhibits post-ischemic tissue damage by inhibiting both xanthine oxidase and O.sub.2.sup.- production by activated polymorphonuclear leukocytes.
Azapropazone is a nonsteroidal anti-inflammatory drug efficacious in treating gouty arthritis by virtue of its ability to inhibit xanthine oxidase and increase the renal excretion of uric acid (Templeton, J. S.: "Azapropazone, In Anti-Rheumatic Drugs," Vol. 3 (Edited by E. C. Huskisson), Praeger Publishers, New York, p. 97 (1983); U.S. Pat. Nos. 3,349,088, 3,482,024, and 4,305,942).
It has now been found that azapropazone also has the unique feature of inhibiting a variety of neutrophil functional responses including the generation of oxygen free radicals. Moreover, the concentrations of azapropazone found to inhibit neutrophil O.sub.2.sup.- production as well as xanthine oxidase in vitro correlate well with the therapeutic plasma levels attained in man. Based upon azapropazone's ability to inhibit both sources of toxic O.sub.2.sup.- radicals, this drug will have distinct and novel therapeutic advantage over the current therapies used in treating ischemic and post-ischemic tissue damage. Specifically, azapropazone would be beneficial in myocardial ischemia and reperfusion due to occlusion and subsequent recanalization of one or more coronary arteries, as well as in myocardial damage due to coronary artery occlusion by itself.